Syphilis Pathogenesis: Host Interactions, Immune Evasion, and Persistence of Treponema pallidum

Treponema pallidum subsp. pallidum is the causative agent of syphilis, a chronic and potentially devastating infection that is resurging globally. The bacterium is highly invasive, disseminates rapidly, and establishes decades-long latency that may progress to severe tissue destruction and death. T. pallidum ’s reduced genome contributes to its dependence on the host. Its impressive TprK antigenic variation, scarce outer membrane proteins, and periplasmic flagella provide for immune evasion, enabling persistence and reinfection. Our understanding of syphilis pathogenesis derives largely from experimental infection in rabbits and from historical studies in humans, though recent advances in continuous cultivation, genetic manipulation, hybrid-capture genome sequencing, and multi-omic approaches have opened new avenues for dissecting host–pathogen interactions and disease pathogenesis. This review highlights mechanisms of syphilis pathogenesis, the central role of the immune response in disease causation and progression, and the role of new technologies in answering long-standing questions and informing vaccine development.